The goals of this project are to detect and accurately describe menstrually-related mood disorders, explore their pathophysiology and response to pharmacological and environmental manipulation, and to document the relationship between reproductive endocrine change and disorders of mood as a way of further investigating the neurobiology of psychiatric illness. In the past year we have identified: 1) differential susceptibility to the mood destabilizing effects of gonadal steroids in 22 patients with history of premenstrual syndrome compared with 18 controls; 2) absence of a mood destabilizing effect of placebo in the hormone replacement phase of the Lupron protocol; 3) elimination of stimulated activation of regional cerebral blood flow by Lupron, with restoration of normal activation by estrogen and progesterone in 11 women; 4) reversal by metergoline of the efficacy of fluoxetine in patients with premenstrual syndrome; 5) significant reductions in plasma testosterone in women with PMS compared with controls across the menstrual cycle, with no group-related differences in plasma ACTH or beta endorphin; 6) absence of diagnosis-related differences in GnRH stimulated LH in PMS patients and controls; 7) evidence of glucocorticoid receptor down regulation and pituitary adrenal activation during estrogen replacement compared with Lupron-induced hypogonadism; 8) preliminary evidence of the ability of hypogonadal women to successfully distinguish estrogen from placebo in a drug discrimination paradigm; 9) preliminary evidence of luteal phase-related impaired capacity to respond to mood induction in women with PMS; 10) preliminary evidence of the ability of an endocrine model of pregnancy to precipitate depression in women with a history of postpartum depression but not controls.